Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction Obesity has reached epidemic proportions world-wide, and has led to a parallel rise in the prevalence of type 2 diabetes mellitus (T2D), together with an associated risk of cardiovascular disease and death. The risk for heart failure in obesity is greater than can be accounted for by traditional risk factors such as hypertension and coronary artery disease. Altered substrate metabolism is thought to contribute importantly to dysfunction of the obese and diabetic heart; however, the exact mechanism leading to dysfunction remains incompletely understood. One increasingly popular theory involves lipid overstorage (termed steatosis) and lipotoxic injury to cardiomyocytes. These data have been derived almost entirely using pre-clinical rodent models however, with translational human research being far less developed. Attempts to translate this work to human subjects have been limited to correlations in patient groups with various underlying co-morbidities. To address this major limitation, we propose a novel and innovative food restriction model, which reproducibly causes a transient, physiological increase in myocardial triglyceride content in young healthy individuals. This experimental approach will provide the most controlled environment to test if myocardial steatosis is directly related to cardiac dysfunction?independent of underlying co-morbidities. Our preliminary data suggest that when exposed to acute lipid overstorage, men?but not premenopausal women? develop LV diastolic dysfunction. Based on this observation we will: 1) Test the hypothesis that cardiac steatosis induced left ventricular dysfunction is sexually dimorphic, by comparing age-matched men and premenopausal women before and after an acute fasting intervention. 2) Test the hypothesis that estrogen is protective against cardiac steatosis-induced dysfunction, by suppressing ovarian sex hormones with a GnRH antagonist and repeating the fasting studies with and without estrogen add-back. 3) Test whether plasma and myocardial fatty acid composition is sexually dimorphic, by performing comprehensive plasma and myocardial lipidomics assessment. The results will provide new and important mechanistic insight into the independent role of myocardial steatosis and its influence on cardiac function in otherwise healthy young human subjects. The results also promise to address the NIH mandate focusing on the influence of sex on disease risk. Taken together, these novel and innovative studies will facilitate paradigm-changing diagnosis and treatment approaches to reduce the burden of heart disease in obesity and diabetes.